Ophthalmic devices containing heterocyclic compounds and methods for their production

ABSTRACT

This invention relates to ophthalmic devices and methods for their production where the ophthalmic device contain a polymer and at least one heterocyclic compound comprising at least one N—Cl and/or N—Br bond.

RELATED PATENT APPLICATIONS

[0001] This patent application claims priority of a provisionalapplication, U.S. Ser. No. 60/348,585 which was filed on Jan. 14, 2002.

FIELD OF THE INVENTION

[0002] This invention relates to opthalmic devices having antimicrobialproperties as well as methods of their production, use, and storage.

BACKGROUND OF THE INVENTION

[0003] Contact lenses have been used commercially to improve visionsince the 1950s. The first contact lenses were made of hard materials.Although these lenses are currently used, they are not suitable for allpatients due to their poor initial comfort and their relatively lowpermeability to oxygen. Later developments in the field gave rise tosoft contact lenses, based upon hydrogels, which are extremely populartoday. Many users find soft lenses are more comfortable, and increasedcomfort levels allow soft contact lens users to wear their lenses forfar longer hours than users of hard contact lenses.

[0004] Despite this advantage, the extended use of the lenses canencourage the buildup of bacteria or other microbes, particularly,Pseudomonas aeruginosa, on the surfaces of soft contact lenses. Thebuild-up of bacteria or other microbes is not unique to soft contactlens wearers and may occur during the use of hard contact lenses aswell.

[0005] Therefore, there is a need to produce contact lenses that inhibitthe growth of bacteria or other microbes and/or the adhesion ofbacterial or other microbes on the surface of contact lenses. Furtherthere is a need to produce contact lenses which do not promote theadhesion and/or growth of bacteria or other microbes on the surface ofthe contact lenses. Also there is a need to produce contact lenses thatinhibit adverse responses related to the growth of bacteria or othermicrobes.

[0006] Others have recognized the need to produce soft contact lensesthat inhibit the growth of bacteria. In U.S. Pat. No. 5,213,801, theproduction of an antibacterial contact lens is disclosed, where anantibacterial metal ceramic material is incorporated into a contactlens. This procedure contains a number of steps and may not be suitablefor producing all types of lenses in a production environment. The stepsinclude making a silver ceramic material that is fine enough to be usedin a contact lens and then forming the lens with the powdered ceramic.However, lenses containing these types of materials often lack theclarity required by contact lens users.

[0007] U.S. Pat. No. 5,808,089; 5,902,818 and 6,020,491 discloseN-halamine type compounds and their use as biocides. Inclusion of thesecompounds in ophthalmic devices is not suggested. U.S. Pat. No.6,162,452 discloses cyclic N-halamine biocidal monomers and polymers.Materials suitable for contact lenses are not disclosed.

[0008] Although these methods and lenses are known, other contact lensesthat inhibit the growth and/or adhesion of bacteria or other microbesand are of sufficient optical clarity, as well as methods of makingthose lenses are still needed. It is this need, which this inventionseeks to meet.

SUMMARY OF THE INVENTION

[0009] This invention includes an opthalmic device comprising,consisting essentially of, or consisting of a polymer and at least oneheterocyclic compound comprising at least one N—Cl bond and/or N—Brbond. Preferably said heterocyclic compound comprises at least onesubstituted five or six membered ring comprising at least one N—Cl bond,at least 3 carbon atoms, 1 to 3 heteroatom nitrogens, 0 to 1 heteroatomoxygen, 0 to 1 heteroatom sulfur and 0 to 3 carbonyls. In anotherembodiment, the heterocyclic compound is a compound of Formula I

[0010] wherein X is independently selected from N, O, C, S;

[0011] at least one of R¹ and R², R⁴ and R⁵ or R⁶ and R taken togetheris a carbonyl, R³ is Cl or Br when X is N and the remainder of R¹-R² andR⁴-R⁷ are independently selected from hydrogen or substituted orunsubstituted C₁₋₄alkyl, Cl, Br, cycloalkyl, substituted orunsubstituted phenyl, substituted or unsubstitute benzyl, ethylenicallyunsaturated alkyl, acryloxyalkyl, oxygen, nitrogen, sulfur containinggroups and the like.

[0012] In a preferred embodiment X is N or O, at least one of R¹ and R²or R⁴ and R⁵ taken together is a carbonyl, R³ is Cl when X is N and theremainder of R¹-R⁷ are independently selected from the group consistingof H, methyl and carbonyl.

[0013] Other suitable heterocyclic compounds include those disclosed inU.S. Pat. No. 6,294,185 and U.S. Pat. No. 6,162,452, the disclosure ofwhich is incorporated herein by reference.

DETAILED DESCRIPTION OF THE INVENTION

[0014] Unless specifically defined otherwise, the following terms havethe meanings set forth below.

[0015] The term heterocyclic compounds include alicyclic ring compoundscomprising at least one ring with three to eight carbons and at leastone heteroatom per ring.

[0016] Cycloalkyl means substituted and unsubstituted alicycliccompounds having three to eight carbon atoms per ring.

[0017] Acryloxyalkyl means substituted or unsubstituted acrylates havinga C₁₋₃ alkyl group adjacent to the oxy group.

[0018] Oxygen containing group include any group which comprise oxygenand carbon and/or hydrogen. Suitable oxygen containing groups includehydroxy, oxo, oxa, alkanoyl, haloalkanoyl, carboxy, alkoxycarbonylgroups, acid anhydrides combinations thereof and the like.

[0019] Sulfur containing group mean any group which comprise at leastone sulfur and hydrogen and may further contain carbon, hydrogen and/oroxygen. Suitable sulfur containing groups include mercapto, alkylthio,sulfate, sulfonic acid groups, combinations thereof and the like.Preferred groups include mercapto and alkylthio.

[0020] Nitrogen containing group mean any group which comprises nitrogenand any combination of carbon, hydrogen and/or oxygen. Suitable nitrogencontaining groups include amino, cyano, carbomoyl, nitro groups,combinations thereof and the like. Preferred groups are amino andcarbamoyl groups.

[0021] It should be appreciated that any of the above may be bridginggroups through which the heterocyclic compounds are linked to theselected polymer.

[0022] In yet another embodiment the heterocyclic compound is selectedfrom 3-chloro-4,4-dimethyl-2-oxazolidinone,1,3-dichloro-4,4,5,5-tetramethyl-2-imidazolidinone,1,3-dichloro-5,5-dimethyl-2,4-imidazolidinedione and1,3-dichloro-2,2,5,5-tetramethyl-4-imidazolidinone and theirpolymerizable derivatives,3-chloro-4-(acryloxymethyl)-4-ethyl-2-oxazolidinone andpoly(1,3-dichloro-5-methyl-5-(4′-vinylphenyl)hydantoin and combinationsthereof.

[0023] As used herein, the term “ophthalmic device” includes devicesthat reside in, on or in front of the eye, such as lenses and relateddevices such as lens cases. The lenses can provide optical correction ormay be cosmetic. The term lens includes, but is not limited to softcontact lenses, hard contact lenses, intraocular lenses, overlay lenses,ocular inserts, optical inserts, spectacle lenses, goggles, surgicalglasses and the like. In a preferred embodiment the ophthalmic device isa contact lens and more preferably a soft contact lens. Soft contactlenses are made from hydrogels and silicone elastomers or hydrogels,which include but are not limited to silicone hydrogels andfluorohydrogels. These hydrogels contain hydrophobic and/or hydrophilicmonomers that are covalently bound to one another in the cured lens. Asused herein the term “lens polymer” means copolymers, homopolymers, ormixtures of said hydrogels and/or silicone elastomers.

[0024] As used herein, unless otherwise specified, all weight percentsmean weight percent based upon the weight of all components present.

[0025] More specifically suitable lens polymers include the soft contactlens formulations described in U.S. Pat. No. 5,710,302, WO 9421698, EP406161, JP 2000016905, U.S. Pat. No. 5,998,498, U.S. Pat. App. No.09/532,943 and U.S. Pat. No. 6,087,415 as well as soft contact lensformulations such as, but are not limited to, etafilcon A, genfilcon A,lenefilcon A, polymacon, aquafilcon A, balafilcon A, and lotrafilcon A.Preferable lens polymers include etafilcon A, balafilcon A, and siliconehydrogels, as prepared in U.S. Pat. No. 5,760,100; U.S. Pat. No.5,776,999; U.S. Pat. No. 5,849,811; U.S. Pat. No. 5,789,461; WO0127174Al and U.S. Pat. No. 6,087,415. These patents are hereby incorporated byreference for the hydrogel compositions contained therein. Lensesprepared from the aforementioned formulations and the heterocycliccompound of the present invention may be coated with a number of agentsthat are used to coat lenses. For example, the procedures, compositions,and methods of U.S. Pat. Nos. 3,854,982; 3,916,033; 4,920,184; and5,002,794; 5,712,327; and 6,087,415 as well as WO 0127662, may be usedand these patents are hereby incorporated by reference for thoseprocedures, compositions, and methods. In addition to the cited coatingpatents, there are other methods of treating a lens once it is formed.The lenses of this invention may be treated by these methods, which areillustrated in U.S. Pat. No. 5,453,467; U.S. Pat. No. 5,422,402; WO9300391; U.S. Pat. No. 4,973,493; and U.S. No. Pat 5,350,800, thedisclosure of which are hereby incorporated by reference in theirentirety.

[0026] Hard contact lenses are made from polymers that include but arenot limited to polymers of poly(methyl)methacrylate, silicon acrylates,fluoroacrylates, fluoroethers, polyacetylenes, and polyimides, where thepreparation of representative examples may be found in JP 200010055; JP6123860; and U.S. Pat. No. 4,330,383. Intraocular lenses of theinvention can be formed using known materials. For example, the lensesmay be made from a rigid material including, without limitation,polymethyl methacrylate, polystyrene, polycarbonate, or the like, andcombinations thereof. Additionally, flexible materials may be usedincluding, without limitation, hydrogels, silicone materials, acrylicmaterials, fluorocarbon materials and the like, or combinations thereof.Typical intraocular lenses are described in WO 0026698; WO 0022460; WO9929750; WO 9927978; WO 0022459; and JP 2000107277. All of thereferences mentioned in this application are hereby incorporated byreference in their entirety.

[0027] The heterocyclic compounds may be incorporated into the selectedpolymer by a number of methods. For example, the heterocycliccompound(s) may be dispersed or dissolved into the monomer and/orprepolymer mixtures (reactive mixtures), which are used to form theopthalmic device. The heterocyclic compounds may contain polymerizablegroups, which will bond to the selected reactive mixture componentsduring processing or may be devoid of polymerizable groups. Preferredpolymerizable heterocyclic compounds have at least one ethylenicallyunsaturated group that allows covalent incorporation of the compoundinto the lens matrix or onto the lens surface. Suitable ethylenicallyunsaturated groups include methacrylates, acrylates, styrenes, mixturesthereof and the like. The ethylenically unsaturated groups may bedirectly linked to the heterocyclic compounds or may include interveningbranched or unbranched alkyl chains, substituted or unsubstituted arylgroups, polyethers, polyamides, polyesters and the like. Heterocycliccompounds which are devoid of polymerizable groups become entangledwithin the lens material when the monomer is polymerized, forming asemi-interpenetrating network.

[0028] Any amount of heterocyclic compound which provides the desiredlevel of inhibition of microbial growth but does not degrade theperformance characteristics (such as, but not limited to modulus) of theresulting device may be used. In certain embodiments amounts betweenabout 1 and about 100,000 ppm are desirable, with amounts between about1 and about 30,000 ppm being preferable and amounts between about 10 andabout 25,000 ppm being more preferred. Conventional tools, such asmixing, milling, adjusting the temperature and pressure during mixing,may be used to incorporate the heterocyclic compound into the reactivemixture. Once the heterocyclic compound is incorporated into thereactive mixture, the reactive mixture is used to form the desireddevice, using known techniques. Thus, where the device is a lens, thereactive mixture may be polymerized and molded or cast into the desiredlens shape, molded or cast into a blank and lathed into the desiredshape, all using conventional conditions which are well known in theart.

[0029] Another method for incorporating the heterocyclic compound intothe ophthalmic device is to add a polymerized heterocyclic compound tothe reactive mixture and form the mixture into a device as describedabove. Polymerized heterocyclic compounds that can be incorporated inthis manner include as at least one of R¹-R⁷, polymerizableethylenically unsaturated moiety, preferably methacrylate, acrylate,methacrylamide, styryl, N-vinyl amide, N-vinyl lactams, vinylcarbonates, vinyl carbamates, maleate, or fumarate. The polymer maycontain other monomers such as N-vinyl pyrrolidone, HEMA, and the like.In addition, the polymer may contain ethylenically unsaturated moietiessuch that it can function as a macromer.

[0030] Yet another method for incorporating the heterocyclic compound isto deposit the heterocyclic compound on the surface of the opthalmicdevice. This can be done by numerous ways. For example, a heterocycliccoating composition, including a polymerizable or prepolymerizedheterocyclic compound, may be formed and coated onto the opthalmicdevice and if desired subjected to conditions sufficient to causepolymerization. Suitable heterocyclic coating compositions include, butare not limited to copolymers of HEMA and polymerizable heterocycliccompounds. It should be appreciated that the heterocyclic compound maybe included in the lens polymer and coated on the lens.

[0031] The coating step may be accomplished by mold transfer, dipcoating, spray coating, photo grafting, thermal grafting and the like.Alternatively, the heterocyclic compound may be covalently attached tothe ophthalmic device via a wet finishing process, such as is disclosedin U.S. Pat. No. 6,077,319, which is incorporated herein by reference.

[0032] Generally a coating effective amount of the coating is used. Acoating effective amount of the heterocyclic compound or heterocyclicamine precursor compound is an amount that when contacted with at leastone surface of the lens is sufficient to coat that surface so as toimpart the desired antimicrobial properties to the surface. The coatingmay be a homopolymer made from polymerized heterocyclic compound orpolymerized heterocyclic amine precursor compound, a copolymer ofpolymerizable heterocyclic compound or polymerizable heterocyclic amineprecursor compound with other polymers, such as but not limited topolyHEMA, polyacrylic acid, PVP, combinations thereof and the like. Thedesired coating compounds may be dissolved in volatile solvents, whichare suitable for coating contact lenses and are known in the art. Byantimicrobial properties is meant either or both the ability tosignificantly reduce, meaning by greater than about 25 percent, eitheror both the amount of bacteria adhering to the surface and the growth ofbacteria adhered to the surface. In the case of contact lenses,generally, the amount contacted with the lens is about 1 μg to about 10mg, preferably about 10 μg to about 1 mg per lens. The amount of coatingresulting per contact lens is about 50 to about 1000 μg. Coatings of thepresent invention comprise between about 1000 μg heterocyclic compoundor heterocyclic amine precursor compound.

[0033] It should be appreciated that, for any of the methods ofincorporation described above, the heterocyclic compound may be addedwith the chlorine or bromine atom already attached to the nitrogen orwithout. If the heterocyclic compound does not contain at least onechlorine when it is incorporated into the device, the device containingthe heterocyclic compound will need to be “charged” by contact with asuitable chlorine source. Suitable chlorine source contain anywhere upto about 50,000 ppm sodium or calcium hypochlorite in aqueous solution,from about 10 ppm to 1000 ppm sodium dichloroisocyanurate and/ortrichloroisocyanuric acid in aqueous solution and other N-chloramines.The chlorine source also comprises a liquid medium such as, but notlimited to, water, deionized water, aqueous buffered solutions,alcohols, polyols, polyethers, glycols and mixtures thereof. Preferredmedia include deionized water and aqueous buffered solutions. It shouldbe appreciated that as the chlorine concentration increases, the contacttime with the solution will decrease. Once the device is charged (orrecharged) it is rinsed with an ophthalmically compatible salinesolution to remove unbound chlorine and ready the device for use (orreuse). The chlorine charging may take place at any point in theprocess, but convenient points include during release from the mold,during wet storage, during hydration of a dry stored lens and as aseparate step after some period of storage or use. It should beappreciated that a single device, and particularly a single lens couldbe recharged a multiple of times to extend its antimicrobialeffectiveness.

[0034] The terms “antimicrobial”, “reduction in microbial activity” and“inhibition of microbial activity” refer to a device that exhibit one ormore of the following properties—the inhibition of the adhesion ofbacteria or other microbes to the ophthalmic device, the inhibition ofthe growth of bacteria or other microbes on the ophthalmic device, andthe killing of bacteria or other microbes on the surface of theophthalmic device or in a radius extending from the ophthalmic device.The lenses of the invention inhibit the microbial activity by at least25%. Preferably, the lenses of the invention exhibit at least a 1-logreduction (≧90% inhibition) of viable bacteria or other microbes, morepreferably a 2-log reduction (≧99% inhibition) of viable bacteria orother microbes. Such bacteria or other microbes include but are notlimited to those organisms found in the eye, particularly Pseudomonasaeruginosa, Acanthamoeba species, Staphyloccus. aureus, E. coli,Staphyloccus epidermidis, and Serratia marcesens. Preferably, saidantimicrobial lens is a clear lens, that has clarity comparable tolenses such as those formed from etafilcon A, genfilcon A, lenefilcon A,polymacon, acquafilcon A, balafilcon A, and lotrafilcon A.

[0035] The advantages of the antimicrobial lenses of the presentinvention are many. Without being bound to any particular theory, it isbelieved that reduction of bacterial activity on the lenses shouldreduce the occurrence of adverse responses related to bacterialadhesion. It is believed that the heterocyclic compounds of the presentinvention reduce microbial activity by slow release of small quantitiesof HOCl, which is an antimicrobial substance produced by the body tokill bacteria. Thus, the lenses of the present invention mimic the eye'schemical response to microbial activity. In addition hypochlorous acidis not known to induce resistance in bacteria. It is further believedthat the halamine moiety (N—X, where X is Br or Cl) of the heterocycliccompounds of the present invention interact directly with bacteria tofurther reduce microbial activity.

[0036] The heterocyclic compounds may also be ‘recharged’ to provideantimicrobial activity throughout the life of the lens. Theantimicrobial lenses of the invention. have comparable clarity to lensessuch as those formed from etafilicon A, genfilcon A, lenefilcon A,polymacon, acquafilcon A, balafilcon A, and lotrafilcon A.

[0037] Further, the invention includes a method of producing anantimicrobial lens comprising a polymer and at least one heterocyclicamine precursor, wherein said hydrogen can be readily replaced with achlorine or bromine ion, wherein the method comprises, consistsessentially of, or consists of the steps of

[0038] (a) preparing a lens comprising a lens polymer and at least oneheterocyclic amine precursor and

[0039] (b) contacting said lens with a chlorine or bromine source.

[0040] The heterocyclic amine precursor has the same structure as theheterocyclic compound defined above, except that the halogen is replacedwith a H. Methods for their preparation are known in the art and aregenerally disclosed in U.S. Pat. No. 6,162,452, which is incorporatedherein by reference. The terms lens and chlorine or bromine source, allhave the meanings defined above. The heterocyclic amine precursor may bepolymerized into the lens polymer, prepolymerized and incorporated intothe reaction mixture, which is then polymerized to form aninterpenetrating network with the polymer or covalently appended to thelens polymer or coated onto the lens surface either in monomeric orpolymeric form or any combination of the above, all as described above.

[0041] Typically, the contacting step is conducted for about 120minutes, though the time may vary from about 1 minute to about 4 hoursand at temperatures ranging from about 5° C. to about 130° C. After thecontacting step the lenses are washed with several portions of water toobtain a lens that is fully charged with chlorine and substantially freefrom unbound chlorine.

[0042] Still further, the invention includes a lens case comprising,consisting essentially of, a lens case polymer and at least oneheterocyclic compound comprising at least one N—Cl or N—Br bond. Theterm lens case refers to a container that is adapted to define a spacein which to hold a lens when that lens is not in use. This term includespackaging for lenses, where packaging includes any unit in which a lensis stored after curing. Examples of this packaging include but are notlimited to single use blister packs, multiple use storage cases and thelike. Suitable containers may have multiple parts such as the outercontainer, which holds the lens, a cover and a lens basket, whichsupports the lens within the chamber inside the container. Theheterocyclic compound can be incorporated in any of these parts, but ispreferably incorporated into the lens container or the lens basket.

[0043] Suitable lens case polymers include, but are not limited tothermoplastic polymeric material, such as polymethylmethacrylate,polyolefins, such as polyethylene, polypropylene, their copolymers andthe like; polyesters, polyurethanes; acrylic polymers, such aspolyacrylates and polymethacrylates; polycarbonates and the like and ismade, or any combination thereof, e.g., molded, using conventionaltechniques as a single unit.

[0044] The heterocyclic compound may be incorporated into the lenscontainer in the same manner that it is incorporated into theantimicrobial lenses of the invention. More specifically, theheterocyclic compound is combined (either as a polymerizable ornon-polymerizable compound) with the formulation of the othercomponents, molded and cured. Preferably the heterocyclic compound ispresent in any or all of the lens case components at about 0.01 to about10.0 weight percent (based on the initial monomer mix), more preferablyabout 0.01 to about 1.5 percent. Storing lenses in such an environmentinhibits the growth of bacteria on said lenses and adverse effects thatare caused by the proliferation of bacteria. Another example of such alens case is the lens case can be found in U.S. Pat. No. 6,029,808 whichis hereby incorporated by reference for the blister pack housing for acontact lens disclosed therein.

[0045] Yet still further, the invention includes a method of reducingthe adverse effects associated with microbial production in the eye of amammal, comprising, consisting essentially of, or consisting ofproviding, for use in or on the eye, an antimicrobial lens wherein saidlens comprises polymer and at least one heterocyclic compound comprisingat least one N—Cl or N—Br bond.

[0046] The terms lens, antimicrobial, lens, R¹-R⁷, all have theiraforementioned meanings and preferred ranges. The phrase “adverseeffects associated with microbial production” includes but is notlimited to, ocular inflammation, contact lens related peripheral ulcers,contact lens associated red eye, infiltrative keratitis, and microbialkeratitis.

[0047] In order to illustrate the invention the following examples areincluded. These examples do not limit the invention. They are meant onlyto suggest a method of practicing the invention. Those knowledgeable incontact lenses as well as other specialties may find other methods ofpracticing the invention. However, those methods are deemed to be withinthe scope of this invention.

[0048] Abbreviations

[0049] The following abbreviations were used in the examples:

[0050] Blue HEMA=the reaction product of reactive blue number 4 andHEMA, as described in Example 4 or U.S. Pat. No. 5,944,853

[0051] CGI 1850=1:1 (w/w) blend of 1-hydroxycyclohexyl phenyl ketone andbis (2,6-dimethyoxybenzoyl)-2,4-4-trimethylpentyl phosphine oxide

[0052] Dl water=deionized water

[0053] D3O=3,7-dimethyl-3-octanol

[0054] DMA=N,N-dimethylacrylamide

[0055] HEMA=hydroxyethyl methacrylate

[0056] IPA=isopropyl alcohol

[0057] mPDMS=mono-methacryloxypropyl terminated polydimethylsiloxane (MW800-1000)

[0058] Norbloc=2-(2′-hydroxy-5-methacrylyloxyethylphenyl)-2H-benzotriazole

[0059] ppm=parts per million micrograms of sample per gram of dry lens

[0060] PVP=polyvinylpyrrolidinone (K 90)

[0061] TBACB=tetrabutyl ammonium-m-chlorobenzoate

[0062] TEGDMA=tetraethyleneglycol dimethacrylate

[0063] THF=tetrahydrofuran

[0064] TRIS=tris(trimethylsiloxy)-3-methacryloxypropylsilane

[0065] TMI=dimethyl meta-isopropenyl benzyl isocyanate

[0066] w/w=weight/total weight

[0067] The following compositions were prepared for use:

[0068] Packing Solution

[0069] Packing solution contains the following ingredients in deionizedH₂O:

[0070] 0.18 weight % sodium borate [1330-43-4], Mallinckrodt

[0071] 0.91 weight % boric acid [10043-35-3], Mallinckrodt

[0072] 0.83 weight % sodium chloride [7647-14-5], Sigma

[0073] 0.01 weight % ethylenediaminetetraacetic acid [60-00-04] (EDTA),Aldrich

[0074] Phosphate Buffered Saline (PBS)

[0075] PBS contains the following in deionized H₂O:

[0076] 0.83 weight % sodium chloride [7647-14-5], Sigma

[0077] 0.05 weight % monobasic sodium phosphate [10049-21-5], Sigma

[0078] 0.44 weight % dibasic sodium phosphate [7782-85-6], Sigma

[0079] Special Packing Solution (SPS)

[0080] SPS contains the following in deionized H₂O:

[0081] 0.18 weight % sodium borate [1330-43-4], Mallinckrodt

[0082] 0.91 weight % boric acid [10043-35-3], Mallinckrodt

EXAMPLE 1

[0083] Preparation of 4-hydroxymethyl-4-ethyl-2-oxazolidinone

[0084] To a 100 mL round bottom flask, equipped with a magnetic stir barwere added 2-amino-2-ethyl-1,3-propanediol (Aldrich lot 10129PN, 80%w/w, 17.12 9, 0.115 moles), sodium methoxide (Aldrich lot 906641, 0.100g, 0.0019 moles), and diethyl carbonate (Aldrich lot 10113EU, 17.5 mL,0.144 moles). The flask was fitted with a reflux condenser and anitrogen inlet, and the contents were refluxed for 48 hours. The refluxcondenser was then replaced with a distillation condenser, and theethanol formed as a by-product in the reaction was distilled off. Thereaction mixture was diluted with 100 mL ethyl acetate, and then pouredinto 400 mL diethyl ether. Upon vigorous stirring, a precipitate formed,which was filtered out, washed with diethyl ether (2×50 mL), and driedto obtain a white solid (14.4 g, 86.3% yield). Structure (Formula 2) wasconfirmed via ¹H NMR and ¹³C NMR data.

[0085] Formula 2. 4-hydroxymethyl-4-ethyl-2-oxazolidinone

EXAMPLE 2

[0086] Preparation of 4-acryloxymethyl-4-ethyl-2-oxazolidinone

[0087] To a 100 mL round bottom flask equipped with a magnetic stir barwere added 4-hydroxymethyl-4-ethyl-2-oxazolidinone (3.10 g, 21.4 mmol)and 40 mL methylene chloride (Aldrich, A.C.S. reagent grade). Acryloylchloride (Aldrich lot 14328BO, 1.80 mL, 22.2 mmol) was added viasyringe. The reaction flask was fitted with a reflux condenser and anitrogen inlet, and the contents were refluxed. After 20 hours, afurther 0.45 mL of acryloyl chloride was added, and the reactionrefluxed for a further 4 hours. Solvents were removed in vacuo using aroto-evaporator to yield a pale yellow oil, which was dissolved in 50 mLmethylene chloride and extracted with 0.1 N NaOH (3×50 mL), andsaturated sodium chloride solution (1×50 mL). The organic layer wasdried over anhydrous sodium sulfate, filtered, and the solvent wasremoved in vacuo using a roto-evaporator to yield clear, pale yellow oil(2.96 g, 69.5% yield). Structure (Formula 3) was confirmed via ¹H NMRand ¹³C NMR data.

[0088] Formula 3. 4-acryloxymethyl-4-ethyl-2-oxazolid inone

EXAMPLE 3

[0089] To a dry container housed in a dry box under nitrogen at ambienttemperature was added 30.0 g (0.277 mol) ofbis(dimethylamino)methylsilane, a solution of 13.75 ml of a 1 M solutionof TBACB (386.0 g TBACB in 1000 ml dry THF), 61.39 g (0.578 mol) ofp-xylene, 154.28 g (1.541 mol) methyl methacrylate (1.4 equivalentsrelative to initiator), 1892.13 (9.352 mol) 2-(trimethylsiloxy)ethylmethacrylate (8.5 equivalents relative to initiator) and 4399.78 g(61.01 mol) of THF. To a dry, three-necked, round-bottomed flaskequipped with a thermocouple and condenser, all connected to a nitrogensource, was charged the above mixture prepared in the dry box.

[0090] The reaction mixture was cooled to 15° C. while stirring andpurging with nitrogen. After the solution reaches 15° C., 191.75 g(1.100 mol) of 1-trimethylsiloxy-1-methoxy-2-methylpropene (1equivalent) was injected into the reaction vessel. The reaction wasallowed to exotherm to approximately 62° C. and then 30 ml of a 0.40 Msolution of 154.4 g TBACB in 11 ml of dry THF was metered in throughoutthe remainder of the reaction. After the temperature of reaction reached30° C. and the metering began, a solution of 467.56 g (2.311 mol)2-(trimethylsiloxy)ethyl methacrylate (2.1 equivalents relative to theinitiator), 3636.6. g (3.463 mol) n-butylmonomethacryloxypropyl-polydimethylsiloxane (3.2 equivalents relative tothe initiator), 3673.84 g (8.689 mol) TRIS (7.9 equivalents relative tothe initiator) and 20.0 g bis(dimethylamino)methylsilane was added.

[0091] The mixture was allowed to exotherm to approximately 38-42° C.and then allowed to cool to 30° C. At that time, a solution of 10.0 g(0.076 mol) bis(dimethylamino)methylsilane, 154.26 g (1.541 mol) methylmethacrylate (1.4 equivalents relative to the initiator) and 1892.13 g(9.352 mol) 2-trimethylsiloxy)ethyl methacrylate (8.5 equivalentsrelative to the initiator) was added and the mixture again allowed toexotherm to approximately 40° C. The reaction temperature dropped toapproximately 30° C. and 2 gallons of THF were added to decrease theviscosity. A solution of 439.69 g water, 740.6 g methanol and 8.8 g(0.068 mol) dichloroacetic acid was added and the mixture refluxed for4.5 hours to de-block the protecting groups on the HEMA. Volatiles werethen removed and toluene added to aid in removal of the water until avapor temperature of 110° C. was reached.

[0092] The reaction flask was maintained at approximately 110° C. and asolution of 443 g (2.201 mol) TMI and 5.7 g (0.010 mol) dibutyltindilaurate were added. The mixture was reacted until the isocyanate peakwas gone by IR. The toluene was evaporated under reduced pressure toyield an off-white, anhydrous, waxy reactive monomer. The macromer wasplaced into acetone at a weight basis of approximately 2:1 acetone tomacromer. After 24 hrs, water was added to precipitate out the macromerand the macromer was filtered and dried using a vacuum oven between 45and 60° C. for 20-30 hrs.

EXAMPLE 4

[0093] A reaction mixture was formed by adding 80 parts of thecomponents shown in Table 1, in the amounts shown in Table 1 with 20parts 3,7-dimethyl-3-octanol. Specifically, in the following ordermacromer, Norbloc 7966, diluent, TEGDMA, HEMA, DMA, TRIS, and mPDMS wereadded to an amber flask. These components were mixed at 170-300 rpm, at50-55° C., for 90 to 180 minutes. While maintaining mixing, blue HEMAwas added and the components mixed for a further 20 to 75 minutes (at170-300 rpm, 50-55° C.).

[0094] Still with mixing, PVP was added and the mixture stirred foranother 20 to 140 minutes (at 170-300 rpm, 50-55° C.). TABLE 1 ComponentWeight Percent Macromer (Ex 3) 17.98 TRIS 14 DMA 26 mPDMS 28 NORBLOC 2TEGDMA 1 HEMA 5

[0095] To 10 g of the monomer mix above, were added 209.7 mg of4-acryloxymethyl-4-ethyl-2-oxazolidinone (as prepared in Example 2,above), 80 mg of CGI 1850 (Ciba lot#-2W419S), and 100 mg of acetic acid(Fischer Scientific lot #983683). This mixture was mechanically stirredat 50° C. for one hour to homogenize the components. The monomer mix wasdegassed under vacuum for 30 minutes, and used to make lenses in anitrogen box at 60-65° C., utilizing Topas alicyclic copolymer(available from Ticona, grade 5013) (front curve, Power -0.50 D) and(back curve) frames under Philips TLO3 lamps with 30 minutes ofirradiation. The monomer mix and frames were equilibrated in thenitrogen box for 10 minutes prior to assembly. The cured lenses weremanually demolded, and immersed in 150 mL of 60:40 mixture of IPA(Mallinckrodt, Ark. (ACS) grade) and deionized (Dl) water, respectively.The released lenses were transferred into 100 mL of IPA, and thenstepped down into Dl water as follows: i) 100 mL of 75:25 (IPA:DIwater); ii) 100 mL of 50:50 (IPA:DI water); iii) 100 mL of 25:75 (IPA:DIwater); iv) 100 mL of Dl water; v) 100 mL of Dl water; vi) 100 mL of Dlwater; vii) 100 mL of Dl water; viii) 100 mL of Dl water. The lenseswere allowed to equilibrate for 20 minutes in between exchanges. Lensesfrom the last Dl water wash were stored in a 100 mL of fresh Dl water.

EXAMPLE 5

[0096] A hydrogel blend was made from the following monomer mix (allamounts were calculated as weight percent of the total weight of thecombination): 17.98% Macromer (Ex 3), 28.0% mPDMS, 14.0% TRIS, 26.0%DMA, 5.0% HEMA, 1.0% TEGDMA, 5.0% PVP, 2.0% Norbloc, 1.25% acetic acid,1.0% CGI 1850, and 0.02% Blue HEMA; 80 weight percent of the precedingcomponent mixture was further diluted with diluent, 20 weight percent ofD30. The monomer mix was degassed under vacuum at a temperature of 55°C. for at least 30 minutes. The monomer mix was used to prepare lensesusing Topas (Ticona, grade 5013) front curves, and polypropylene (Fina,grade EOD 00-11) back curves. The lenses were cured under visible lightPhilips TL-03 bulbs in a nitrogen atmosphere (<0.5% 02) for 12-15minutes @ 70±5° C.

[0097] The cured lenses were demolded, and then released, leached andhydrated using IPA-deionized water mixtures. The lenses were autoclavedin packing solution for use in microbiological testing.

EXAMPLE 6

[0098] Five lenses, prepared as described in Example 4, were treatedwith 25 mL of dilute sodium hypochlorite solution [1 part Clorox™ bleach(5.25% NaOCl) and 99 parts Dl water] by rolling the solution and lensesin a jar on a jar roller for 2 hours. The solution was then decanted,and the lenses were washed with Dl water (3×30 mL) by rolling the lenseson a jar roller.

[0099] The lenses were autoclaved (30 minutes at 121° C.) in specialpacking solution.

[0100] The autoclaved lenses were analyzed for efficacy against P.aeruginosa using the following method. A culture of Pseudomonasaeruginosa, ATCC#15442 (American Type Culture Collection, Rockville,Md.), was grown overnight in a tryptic soy medium. The bacterialinoculum was prepared to result in a final concentration ofapproximately 1×10⁶ colony forming units/mL (cfu/mL). Three contactlenses were rinsed with phosphate buffered saline (PBS, pH=7.4+/−0.2) toremove residual packing solution. Each rinsed contact lens was placedwith 2 mL of the bacterial inoculum into a sterile glass vial, which wasthen rotated in a shaker-incubator (100 rpm) for two hours at 37+/−2° C.Each lens was removed from the glass vial, rinsed with PBS to removeloosely bound cells, placed into individual wells of a 24-wellmicrotiter plate containing 1 mL PBS, and rotated in a shaker-incubatorfor an additional 22 hours at 37+/−2° C. Each lens was again rinsed withPBS to remove loosely bound cells, placed into 10 mL of PBS containing0.05% (w/v) Tween™ 80, and vortexed at 2000 rpm for three minutes,employing centrifugal force to disrupt adhesion of the remainingbacteria to the lens. The resulting supernatant was enumerated forviable bacteria and the results of detectable viable bacteria attachedto three lenses were averaged and are reported in Table 2, below. Lensesfrom Example 4, autoclaved in special packing solution, were used as thecontrols for microbiological experiments. TABLE 2 Ex# Log CFU¹ Logreduction 4 5.84 Control 6 5.07 0.77

[0101] Thus, the lenses containing N-halamine showed a 0.77 logreduction in microbial adhesion vs. the lens containing the halamineprecursor.

EXAMPLE 7

[0102] Six lenses, prepared as described in Example 4, were treated with100 mL of dilute sodium hypochlorite solution [10 part Clorox™ bleach(5.25% NaOCI) and 90 parts Dl water] by rolling the solution and lensesin a jar on a jar roller for 2.5 hours. The solution was then decanted,and the lenses were washed with Dl water (3×100 mL) by rolling thelenses on a jar roller, allowing one hour for the first wash and twohours for subsequent washes. The lenses were autoclaved in specialpacking solution and analyzed for efficacy using the proceduresdescribed in Example 6. Lenses made according to Example 5 (containingno precursor) were used as controls. The results are listed in Table 3,below. TABLE 3 Ex# Log CFU Log reduction 5 5.96 Control 7 4.41 1.55

[0103] Thus the lenses containing N-halamine showed a 1.55 log reductionvs. the lens containing no halamine.

[0104] Since there was no substantial difference noted between the ‘logCFU’ counts for Example 4 (N-halamine precursor) and Example 5 (nohalamine precursor), the incorporation of N-halamine precursor itselfdoes not confer antimicrobial properties to the lenses.

[0105] A comparison of Examples 6 and 7 suggests that increasing theconcentration of sodium hypochlorite solution used to treat the lensesmay improved efficacy (decrease bacterial adhesion).

What is claimed is:
 1. A lens comprising, a polymer and at least oneheterocyclic compound comprising at least one N—Cl and/or N—Br bond. 2.The lens of claim 1 wherein said at least one heterocyclic compoundcomprises at least one substituted five or six membered heterocyclicring.
 3. The lens of claim 1 wherein said heterocyclic compoundcomprises at least one substituted five or six membered heterocyclicring comprising within said ring at least one N—Cl bond or N—Br bond, atleast 3 carbon atoms, 1 to 3 heteroatom nitrogen containing groups, 0 to1 heteroatom oxygen, 0 to 1 heteroatom sulfur containing groups and 0 to3 carbonyls.
 4. The lens of claim 1 wherein said at least oneheterocyclic compound comprises compound of Formula I,

wherein X is independently selected from N, O, C, S; at least one of R¹and R², R⁴ and R⁵ or R⁶ and R⁷ taken together is a carbonyl, R³ is is Clor Br when X is N and the remainder of R¹-R⁷ are independently selectedfrom the group consisting of hydrogen, substituted or unsubstitutedC₁₋₄alkyl, Cl, Br, cycloalkyl, substituted or unsubstituted phenyl,substituted or unsubstitute benzyl, ethylenically unsaturated alkyl,acryloxyalkyl, oxygen containing groups, sulfur containing groups andnitrogen containing groups.
 5. The lens of claim 2 wherein at least oneR¹ and R² or R⁴ and R⁵ taken together are O; X is N or O and R³ is Clwhen X is N and remaining substituents are independently selected fromhydrogen and methyl.
 6. The lens of claim 2 wherein said at least oneheterocyclic compound is selected from the group consisting of3-chloro-4,4-dimethyl-2-oxazolidinone,1,3-dichloro-4,4,5,5-tetramethyl-2-imidazolidinone,1,3-dichloro-5,5-dimethyl-2,4-imidazolidinedione and1,3-dichloro-2,2,5,5-tetramethyl-4-imidazolidinone and polymerizablederivatives thereof, 3-chloro-4-(acryloxymethyl)-4-ethyl-2-oxazolidinoneand poly(1,3-dichloro-5-methyl-5-(4′-vinylphenyl)hydantoin and mixturesthereof.
 7. The lens of claim 2 wherein said lens is a soft contactlens.
 8. The lens of claim 2 wherein said at least one heterocycliccompound is present in an amount between about 1 to about 100,000 ppm.9. The lens of claim 2 wherein said at least one heterocyclic compoundis present in an amount between about 1 and about 30,000 ppm.
 10. Thelens of claim 2 wherein said at least one heterocyclic compound ispresent in an amount between about 10 and about 25,000 ppm.
 11. The lensof claim 7 wherein, the lens is a silicone hydrogel.
 12. The lens ofclaim 7 wherein, the lens is etafilcon A, balafilcon, A, acquafilcon A,lenefilcon A, or lotrafilcon A.
 13. The antimicrobial lens of claim 7wherein the lens is etafilcon A.
 14. The antimicrobial lens of claim 7wherein the lens is acquafilcon A.
 15. A method of producing a lensformed from a reactive mixture comprising the steps of (a) adding atleast one heterocyclic compound comprising at least one N—Cl and/or N—Brbond to said reactive mixture; and (b) polymerizing said reactivemixture under conditions sufficient to form said lens.
 16. The processof claim 15 wherein said heterocyclic compound further comprises apolymerizable group and wherein said process further comprises the stepof prepolymerizing said heterocyclic compound prior to step (a).
 17. Themethod of claim 16 wherein said polymerizable group comprises at leastone ethylenically unsaturated group.
 18. The method of claim 16 whereinsaid ethylenically unsaturated group is selected from the groupconsisting of methacrylates, acrylates, styrenes and mixtures thereof.19. The method of claim 18 wherein said ethylenically unsaturated groupsfurther comprises a linking moiety selected from the group consisting ofbranched or unbranched alkyl chains, substituted or unsubstituted arylgroups, polyethers, polyamides and polyesters.
 20. A method of producinga coated lens comprising the steps of (a) forming a lens; and (b)coating at least one surface of said lens with a coating compositioncomprising at least one heterocyclic compound comprising at least oneN—Cl and/or N—Br bond.
 21. The method of claim 20 wherein said coatingstep comprises contacting said lens with a coating compositioncomprising at least one heterocyclic amine precursor compound selectedfrom the group consisting of monomeric heterocyclic amine precursorcompounds, polymeric heterocyclic amine precursor compounds andpolymerizable heterocyclic amine precursor compounds and contacting saidcoated lens with a halogen source to form said heterocyclic compound.22. A lens formed from the method of claim
 20. 23. A method of producingan ophthalmic device formed from a reactive mixture comprising the stepsof (a) adding at least one heterocyclic amine precursor compoundselected from the group consisting of monomeric heterocyclic amineprecursor compounds, polymeric heterocyclic amine precursor compoundsand polymerizable heterocyclic amine precursor compounds to saidreactive mixture; and (b) polymerizing said reactive mixture underconditions sufficient to form said lens.
 24. The method of claim 23wherein said process further comprises the step of contacting saidophthalmic device with a halogen source. 25 The method of claim 23wherein said halogen source comprises a chlorine or bromine donatingcompound.
 26. The method of claim 23 wherein said chorine or brominedonating compound selected from the group consisting of aqueous sodiumor calcium hypochlorite and sodium dichloroisocyanuarate.
 27. The methodof claim 23 wherein said ophthalmic device is a contact lens, contactlens case or a contact lens basket.
 28. A lens case comprising a polymerand at least one heterocyclic compound comprising at least one N—Cland/or N—Br bond.
 29. A method of reducing microbial adhesion to acontact lens placed in the eye of a mammal comprising providing anantimicrobial lens comprising, a lens polymer and at least oneantimicrobial heterocyclic compound comprising at least one N—Cl and/orN—Br bond.
 30. An lens comprising a lens polymer and at least oneantimicrobial heterocyclic compound comprising at least one N—Cl and/orN—Br bond, wherein said lens inhibits microbial production by at least25%.
 31. The lens of claim 30 wherein said lens inhibits microbialactivity by at least about 50% to at least about 99%.
 32. The lens ofclaim 30 wherein said les inhibits microbial activity by at least about80% to at least about 99%.
 33. A method of producing a coated lenscomprising the steps of (c) forming a lens; and (d) coating at least onesurface of said lens with a coating composition comprising at least oneheterocyclic amine precursor compound selected from the group consistingof monomeric heterocyclic amine precursor compounds, polymericheterocyclic amine precursor compounds and polymerizable heterocyclicamine precursor compounds.
 34. A lens formed from the method of claim33.